Rationale <p>Chronic substance use disrupts autonomic nervous system (ANS) function, altering stress and reward processing. The clinical significance of autonomic responses to alcohol-related stimuli in cocaine use disorder (CUD) remains unclear.</p> Objective <p>This study investigated ANS reactivity to alcohol-related cues and emotional stimuli in individuals with CUD and healthy controls, aiming to characterize specific patterns of autonomic dysregulation and their relationship to craving.</p> Methods <p>Participants with CUD (<i>n</i> = 80) and healthy controls (<i>n</i> = 42) performed two tasks—alcohol cue exposure (ALC) and facial emotion recognition (FER)—in a counterbalanced order. We used mixed linear models and general estimating equations to test task and group effects on heart rate variability (HRV) metrics (Cardiac Vagal Index [CVI] and Cardiac Sympathetic Index [CSI]), subjective craving, and relaxation, controlling for age, sex, and alcohol-use severity (AUDIT score).</p> Results <p>Individuals with CUD exhibited reduced baseline parasympathetic activity and heightened sympathetic tone. They showed lower CVI across both tasks. A task-specific sympathetic increase (higher CSI) was found only during the ALC task. This physiological response was accompanied by increased craving in both conditions. A paradoxical finding revealed that more severe alcohol use disorder (higher AUDIT scores) was associated with lower baseline sympathetic tone. Subjective relaxation ratings dissociated from physiological reactivity, indicating an autonomic response conflict characterized by the co-occurrence of appetitive and stress-related components.</p> Conclusions <p>Results demonstrate a specific autonomic dysregulation pattern in CUD, featuring task-specific sympathetic hyper-reactivity and pervasive vagal withdrawal. This supports the utility of vagal-sympathetic balance assessment and suggests interventions targeting stress resilience.</p>